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Fuelling Drug Discovery Against Mycobacterium Tuberculosis

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Fuelling Drug Discovery Against Mycobacterium Tuberculosis More Medicines for Tuberculosis: Fuelling Drug Discovery against Mycobacterium tuberculosis THÈSE NO 8906 (2018) PRÉSENTÉE LE 5 OCTOBRE 2018 À LA FACULTÉ DES SCIENCES DE LA VIE UNITÉ DU PROF. COLE PROGRAMME DOCTORAL EN BIOTECHNOLOGIE ET GÉNIE BIOLOGIQUE ÉCOLE POLYTECHNIQUE FÉDÉRALE DE LAUSANNE POUR L'OBTENTION DU GRADE DE DOCTEUR ÈS SCIENCES PAR Shi-Yan Caroline FOO acceptée sur proposition du jury: Prof. M. Blokesch, présidente du jury Prof. S. Cole, directeur de thèse Prof. P. Sander, rapporteur Prof. M. Jackson, rapporteuse Prof. K.-H. Altmann, rapporteur Suisse 2018 Summary Tuberculosis (TB), whose etiological agent is Mycobacterium tuberculosis (M. tuberculosis), has plagued humanity since antiquity. Even with chemotherapy available today, TB is the leading cause of death due to an infectious disease. Modern day factors, such as the HIV epidemic and the emergence of drug-resistant TB strains, have redefined the complexities and challenges of tackling the TB pandemic. Current treatments for TB are lengthy, and poor adherence to such prolonged treatment further exacerbates the issue of drug resistance. Moreover, therapies for drug-resistant TB have low cure rates. There is therefore a pressing need for improved therapies that are short and efficacious against all TB strains, which can be achieved through new antimicrobials that are more potent and have novel mechanisms of action, in addition to being affordable, orally bioavailable, and without drug-drug interactions. Such new anti-TB drugs need to be discovered and developed through a long, risky, and costly process, in which attrition rates are high. While there are promising compounds currently being developed, including the benzothiazinones (BTZs), it is necessary to further populate and enhance the Global TB drug pipeline to ensure the availability of new drugs. This thesis aims to address this need through the discovery work of two new, highly promising families, the AX and PB compounds, and of BTZs. The piperazine-based AX analogs are easily synthesised and demonstrate potent activity against M. tuberculosis in vitro and in vivo. Their target, identified in this work, is the QcrB subunit of the cytochrome bc1-aa3 complex, a terminal oxidase of the mycobacterial respiratory chain. Notably, AX compounds are bactericidal in the absence of the alternate terminal oxidase, cytochrome bd. As this family interacts differently in the same binding site of QcrB as Q203, a drug candidate in clinical trials, AX compounds could potentially serve as a backup series for QcrB inhibitors. The PB family, derived from the natural product lapachol, is also easily synthesised and shows substantially improved activity against M. tuberculosis in vitro compared to the parent compound. PB analogs also demonstrated activity against the non-replicating bacillus and in infected macrophages. The mechanism of action of PB compounds relies on the F420 cofactor, although not on the F420-dependent nitroreductase Ddn, therefore this family has a novel mechanism of action which is highly specific to M. tuberculosis. To support the clinical development of PBTZ169, the mechanism of resistance to BTZs was further elucidated in this thesis. Five mutations at cysteine 387 of the target enzyme, DprE1, were identified as mediating resistance to BTZs, which would serve as resistance markers for clinical screening. The impact of these mutations on M. tuberculosis and on DprE1 was further characterised, revealing a fitness cost imposed on the bacillus intracellularly and reduced catalytic efficiency of the enzyme. This thesis additionally contributed to the characterisation of a PBTZ169 backup series and the design of an optimal regimen with other TB drugs. The compounds presented herein merit further optimisation so their full antibiotic potential may be realised for TB, and possibly for other mycobacterial diseases as well. Altogether, this thesis has contributed to the fuelling of drug discovery against M. tuberculosis, and a step towards more medicines for TB. Keywords: tuberculosis, anti-TB drugs, drug discovery and development, drug resistance, QcrB inhibitors, natural product lapachol, F420 cofactor, benzothiazinone, PBTZ169 Résumé La tuberculose (TB), dont l'agent étiologique est Mycobacterium tuberculosis (M. tb), affecte l'humanité depuis l'antiquité. Malgré la disponibilité d’une antibiothérapie, elle est la principale cause de décès dû à une maladie infectieuse. Les facteurs modernes, tels que l'épidémie du VIH et l’apparition de souches multi-résistantes, ont redéfini les défis de la lutte contre la pandémie causée par le bacille de Koch. Les traitements actuels sont longs, et le manque d'observance entraîne la résistance aux antibiotiques. De plus, les traitements contre la TB résistante ont de faibles taux de guérison. Il y a donc un besoin urgent d’améliorer les médicaments offerts afin de diminuer le temps de traitement et d’augmenter l’efficacité de ceux-ci contre l’ensemble des souches de M. tb. Par conséquent, la découverte de nouveaux antimycobactériens abordables, ne présentant aucune interaction médicamenteuse, ayant de nouveaux mode d’actions et biodisponibles par voie orale est l’un des nerfs de la guerre afin de contrer la TB dans le monde. Ces nouveaux médicaments sont mis au point dans le cadre d'un processus long et coûteux dans lequel les taux d'attrition sont élevés. Bien que des composés prometteurs soient en cours de développement, dont les benzothiazinones (BTZ), il est nécessaire d’alimenter le pipeline de nouveaux médicaments contre la TB. Cette thèse répond à cette problématique par la découverte de deux nouvelles familles très prometteuses, les composés AX et PB, ainsi que les BTZ. Les analogues AX sont faciles à synthétiser et démontrent une bonne activité contre M. tb in vitro et in vivo. La cible, identifiée dans ce travail, est la sous-unité QcrB du complexe cytochrome bc1-aa3, une oxydase terminale de la chaîne respiratoire mycobactérienne. Les composés AX sont bactéricides en l'absence de l'oxydase terminale alternative, le cytochrome bd. Puisque cette famille interagit différemment au même site de liaison que le Q203, les composés AX pourraient servir de série alternative pour les inhibiteurs de QcrB. La famille PB est dérivée du lapachol, un produit naturel. Les composés sont facilement synthétisables et présentent une amélioration substantielle de l'activité contre M. tb par rapport au lapachol. Les analogues PB ont démontré une activité contre le bacille non-réplicatif ainsi que dans les macrophages infectés. Le mécanisme d'action repose sur le cofacteur F420, mais est indépendant de la nitroréductase Ddn, ce qui suggère que cette famille possède un nouveau mécanisme d'action très spécifique à M. tb. Pour soutenir le développement clinique du PBTZ169, le mécanisme de résistance aux BTZ a été caractérisé. Cinq mutations de la cystéine 387 de l'enzyme cible, DprE1, ont été identifiées et impliquées dans cette résistance. La présence de ces mutations diminue la virulence ex vivo, ainsi qu’elle altère l’efficacité catalytique de l'enzyme Dpre1. Ces mutations pourraient servir de marqueurs de résistance pour le dépistage clinique. Cette thèse a également contribué à la caractérisation d'une série alternative du PBTZ169 et à la conception d'’une combinaison optimale avec d'autres antituberculeux. Les composés présentés ici méritent d’être améliorés afin que leur activité soit optimale contre M. tb et possiblement contre d’autres mycobactéries. Dans l’ensemble, cette thèse a contribué à la découverte de nouveaux antituberculeux afin d’élargir le spectre des outils permettant de lutter contre la TB. Mots-clés : tuberculose, médicaments antituberculeux, découverte et développement d’antibiotiques, pharmacorésistance, inhibiteur de QcrB, produit naturel lapachol, cofacteur F420, benzothiazinone, PBTZ169 Table of Contents Abbreviations ............................................................................................................................. 3 Chapter 1: Tuberculosis – past and present ................................................................................ 5 Chapter 2: Arylvinylpiperazine amides, a new class of potent inhibitors targeting QcrB of Mycobacterium tuberculosis .................................................................................................... 63 Chapter 3: Discovery of new plant-derived inhibitors with potent F420-dependent activity against Mycobacterium tuberculosis ...................................................................................... 129 Chapter 4: Characterization of DprE1-mediated Benzothiazinone Resistance in Mycobacterium tuberculosis .................................................................................................. 159 Chapter 5: Conclusions and Perspectives ............................................................................... 177 Appendix Chapter A1: Structural studies of Mycobacterium tuberculosis DprE1 interacting with its inhibitors .................................................................................................................... 189 Appendix Chapter A2: Structure-based drug design and characterization of sulfonyl- piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis ............ 199 Appendix Chapter A3: An optimized background regimen for treatment of active tuberculosis with the next-generation benzothiazinone Macozinone (PBTZ169) ..................................... 237 Acknowledgements ...............................................................................................................
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